Quantitative analysis of the open-state affinity of L-type calcium channel blockers and modeling of their inhibitory actions

• Project/Area Number: 21590275
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Shinshu University
• Principal Investigator: YAMADA Mitsuhiko 信州大学, 医学部, 教授 (10263237)
• Co-Investigator(Renkei-kenkyūsha): NAKADA Tsutomu 信州大学, 医学部, 助教 (70452141)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: Ca_V<1. 2> L型カルシウムチャネル / ジヒドロピリジン / 膜電位依存性不活性化 / Timothy症候群 / アロステリックモデル / L型カルシウムチャネル / Ca_v1.2 / 不活性化

Research Abstract

We found that an antihypertensive agent, nifedipine can prevent fatal ventricular arrhythmias. Nifedipine exerts its effect by blocking L-type Ca^<2+> channels, which mediate Ca^<2+> influx into cells. In this study, we introduced genes encoding the channels into cultured cells and analyzed their function, thereby identified the mechanism by which nifedipine causes the effect to prevent fatal ventricular arrhythmias.

Research Products

• [Journal Article] Two mechanistically distinct effects of dihydro pyridine nifedipine on Ca^V〈1. 2〉L-type Ca^<2+> channels revealed by Timothy syndrome mutation (2012)
  • Author(s): Sheng, X., Nakada, T., Kobayashi, M., Kashihara, T., Shibazaki, T., Horiuchi-Hirose, M., Gomi, S., Hirose, M., Aoyama, T., Yamada, M
  • Journal Title: Eur. J. Pharmacol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca^<2+> channel activity through phosphatases in heart failure (2012)
  • Author(s): Kashihara, T., Nakada, T., Shimojo, H., Horiuchi-Hirose, M., Gomi, S., Shibazaki, T., Sheng, X., Hirose, M., Hongo, M., and Yamada, M
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol Volume: 302 Issue: 8 Pages: 1645-1654
  • DOI: 10.1152/ajpheart.00589.2011
  • Peer Reviewed
• [Journal Article] Chronic receptor-mediated activation of G_<i/o> proteins alters basal t-tubular and sarcolemmal L-type Ca^<2+> channel activity through phosphatases in heart failure (2012)
  • Author(s): Kashihara, T.
  • Journal Title: Am.J.Physiol.Heart Circ.Physiol. Volume: 302
  • Peer Reviewed
• [Journal Article] Two mechanistically distinct effects of dihydropyridine nifedipine on Ca_v 1.2 L-type Ca^<2+> channels revealed by Timothy syndrome mutation (2012)
  • Author(s): Sheng, X., et al
  • Journal Title: Eur.J.Pharmacol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Acid-Sensing Ion Channels in Blood Volume Regulation (2011)
  • Author(s): Yamada, M
  • Journal Title: Circulation Journal Volume: 75 Issue: 4 Pages: 781-782
  • DOI: 10.1253/circj.CJ-11-0085
  • NAID: 10028102876
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Diacylglycerol Kinase &zeta; Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure (2011)
  • Author(s): Hirose, M., Takeishi, Y., Niizeki, T., Nakada, T., Shimojo, H., Kashihara, T., Horiuchi-Hirose, M., Kubota, I., Mende, U., Yamada, M
  • Journal Title: Circulation Journal Volume: 75 Issue: 10 Pages: 2333-2342
  • DOI: 10.1253/circj.CJ-10-1213
  • NAID: 10029459214
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Decrease in the density of t-tubular L-type Ca^<2+> channel currents in failing ventricular my cytes (2011)
  • Author(s): Horiuchi-Hirose, M., Kashihara, T., Nakada, T., Kurebayashi, N., Shimojo, H., Shibazaki, T., Sheng, X., Yano, S., Hirose, M., Hongo, M., Sakurai, T., Moriizumi, T., Ueda, H., and Yamada, M
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol Volume: 300(3) Issue: 3 Pages: 978-988
  • DOI: 10.1152/ajpheart.00508.2010
  • Peer Reviewed
• [Journal Article] Thrombin activates Ca^<2+>-permeating nonselective cation channels through protein kinase C in human umbilical vein endothelial cells (2011)
  • Author(s): Tsujino, N, Nakada, T., Tsubouchi, K., Kobayashi, M., Kawai, Y., Yano, S., Matsunaga, T., Hirose, M., Ohmori, S., Ohhashi, T., Yamada, M
  • Journal Title: Shinshu Med. J Volume: 59 Pages: 13-26
  • NAID: 130004810183
  • Peer Reviewed
• [Journal Article] Nicorandil ameliorates impulseconduction disturbances during ischemia in isolated arterially perfused canine atria (2011)
  • Author(s): Hirose, M., Yano, S., Nakada, T., Horiuchi-irose, M., Tsujino, N., Yamada, M
  • Journal Title: Int. J. Cardiol Volume: 146 Issue: 1 Pages: 37-43
  • DOI: 10.1016/j.ijcard.2009.06.011
  • Peer Reviewed
• [Journal Article] Thrombin activates Ca^<2+>-permeating nonselective cation channels through protein kinase C in human umbilical vein endothelial cells. (2011)
  • Author(s): Tsujio, N.
  • Journal Title: Shinshu Medical Journal Volume: 59 Pages: 13-26
  • Peer Reviewed
• [Journal Article] Decrease in the density of t-tubular L-type Ca^<2+> channel currents in failing ventricular myocytes. (2011)
  • Author(s): Horiuchi-Hirose, M., et al.
  • Journal Title: American Journal Physiology Heart and Circulatory Physiology Volume: 300
  • Peer Reviewed
• [Journal Article] Acid-sensing ion channels in blood volume regulation. (2011)
  • Author(s): Yamada, M
  • Journal Title: Circulation Journal Volume: 75 Pages: 781-782
  • NAID: 10028102876
  • Peer Reviewed
• [Journal Article] Mitochondrial ATP-sensitive K^+ channels, protectors of the heart (2010)
  • Author(s): Yamada, M
  • Journal Title: J. Physiol.(Lond) Volume: 582 Issue: 2 Pages: 283-286
  • DOI: 10.1113/jphysiol.2009.179028
  • NAID: 120007110425
  • Peer Reviewed
• [Journal Article] Selectiveα_〈1A〉-adrenoceptor stimulation induces Mueller' s smooth muscle contraction in an isolated canine upper eyelid preparation (2010)
  • Author(s): Yano, S., Hirose, M., Nakada, T., Nakayama, J., Matsuo, K., Yamada, M
  • Journal Title: Curr. Eye Res Volume: 35 Issue: 5 Pages: 363-369
  • DOI: 10.3109/02713680903518858
  • Peer Reviewed
• [Journal Article] Selective α_<1A>-adrenoceptor stimulation induces Mueller's smooth muscle contraction in an isolated canine upper eyelid preparation. (2010)
  • Author(s): Yano, S., et al.
  • Journal Title: Current Eye Research Volume: 35 Pages: 363-369
  • Peer Reviewed
• [Journal Article] Effects of hormone-sensitive lipase-disruption on cardiac energy metabolism in response to fasting and refeeding (2009)
  • Author(s): Suzuki, J., Ueno, M., Uno, M., Hirose, Y., Zenimaru, Y., Takahashi, S., Osuga, J. I., Ishibashi, S., Takahashi, M., Hirose, M., Yamaa, M., Kraemer, F. B., Miyamori, I
  • Journal Title: Am. J. Physiol. Endocrinol. Metab Volume: 297 Pages: 1115-1124
  • Peer Reviewed
• [Journal Article] Diaclglycerol seζinhibits G_〈αq〉-induced atrial remodeling in transgenic mice (2009)
  • Author(s): Hirose, M., Takeishi, Y., Niizeki, T., Shimojo, H., Nakada, T., Kubota, I., Nakayama J., Mende, U., Yamada, M
  • Journal Title: Heart Rhythm Volume: 6 Pages: 78-84
  • Peer Reviewed
• [Journal Article] Diacylglycerol kinase ζ inhibits G_<αq>-induced atrial remodeling in transgenic mice. (2009)
  • Author(s): Hirose, M., et al.
  • Journal Title: Heart Rhythm 6 Pages: 78-84
  • Peer Reviewed
• [Journal Article] Nicorandil ameliorates impulse conduction disturbances during ischemia in isolated arterially perfused canine atria. (2009)
  • Author(s): Hirose, M., et al.
  • Journal Title: Int.J.Cardiol. E-pub(in press)(未定)
  • Peer Reviewed
• [Journal Article] Effects of hormone-sensitive lipase-disruption on cardiac energy metabolism in response to fasting and refeeding. (2009)
  • Author(s): Suzuki, J., et al.
  • Journal Title: Am J Physiol Endocrinol Metab 297
  • Peer Reviewed
• [Journal Article] Mitochondrial ATP-sensitive K^+ channels, protectors of the heart. (2009)
  • Author(s): Yamada, M.
  • Journal Title: J.Physiol.(Lond.) 582 Pages: 283-286
  • NAID: 120007110425
  • Peer Reviewed
• [Presentation] HSF1は老年性心アミロイドーシスによる心臓の電気的・構造的リモデリングを改善する (2012)
  • Author(s): 弘瀬雅教
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本
  • Year and Date: 2012-03-30
• [Presentation] 不全心室筋細胞のT管のL型Ca^<2+>チャネル活性を低下させるG蛋白質共役型受容体の特定 (2012)
  • Author(s): 柏原俊英
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本
  • Year and Date: 2012-03-29
• [Presentation] L型カルシウムチャネルの結合膜局在化におけるジャンクトフィリンの役割 (2012)
  • Author(s): 中田勉
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本
  • Year and Date: 2012-03-29
• [Presentation] L型カルシウムチャネルとリアノジン受容体の結合膜局在化におけるジャンクトフィリンの役割 (2012)
  • Author(s): 中田勉
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-16
• [Presentation] 心不全での慢性的β_2アドレナリンおよびM_2ムスカリン受容体刺激によるT管L型Ca^<2+>チャネルの抑制 (2012)
  • Author(s): 柏原俊英
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-15
• [Presentation] Proximal C-terminus of α1C subunits is necessary for junctional membrane-targeting of cardiac L-type calcium channel (2011)
  • Author(s): Nakada, T.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] Timothy症候群点変異により明らかとなったL型C^<a2+>チャネル阻害薬ニフェジピンの2つの異なる作用機序 (2011)
  • Author(s): 生暁郷
  • Organizer: 第125回日本薬理学会関東部会
  • Place of Presentation: 東京
  • Year and Date: 2011-10-15
• [Presentation] 不全心室筋細胞のT管のL型Ca^<2+>チャネル活性低下への慢性的β_2アドレナリン受容体刺激の関与 (2011)
  • Author(s): 柏原俊英
  • Organizer: 第124回日本薬理学会関東部会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-04
• [Presentation] 心筋L型カルシウムチャネルの結合膜局在化モチーフの探索 (2011)
  • Author(s): 中田勉, 他
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜(誌上開催)
  • Year and Date: 2011-03-24
• [Presentation] β2アドレナリン受容体を介したG_i/o蛋白質の活性化は不全心室筋細胞のT管のL型Ca^<2+>チャネル電流密度を減少させる (2011)
  • Author(s): 柏原俊英, 他
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜(誌上開催)
  • Year and Date: 2011-03-23
• [Presentation] オルメサルタンは心不全モデルマウスにおける心房筋のリモデリングを改善する (2011)
  • Author(s): 弘瀬雅教, 他
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜(誌上開催)
  • Year and Date: 2011-03-23
• [Presentation] Receptor-medated activation of G_<i/o> proteins causes a decrease in the t-tubular L-type Ca^<2+> channel current density in failing ventricular myocytes (2011)
  • Author(s): Toshihide Kashihara, et al.
  • Organizer: 第75回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜(誌上開催)
  • Year and Date: 2011-03-20
• [Presentation] GLT細胞を用いた心筋L型Ca^<2+>チャネルのクラスタリング機構の解析 (2010)
  • Author(s): 中田勉, 他
  • Organizer: 第123回日本薬理学会関東部会
  • Place of Presentation: 栃木
  • Year and Date: 2010-10-23
• [Presentation] 不全心室筋細胞のT管L型Ca^<2+>チャネル電流密度減少機構への百日咳毒素感受性G蛋白質(G_i/o)の関与 (2010)
  • Author(s): 柏原俊英, 他
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
  • Year and Date: 2010-05-21
• [Presentation] ニフェジピンは超遅延性膜電位依存性不活性化を安定化してL型Ca^<2+>チャネルを抑制する (2010)
  • Author(s): 生暁娜, 他
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪
  • Year and Date: 2010-03-17
• [Presentation] 不全心室筋細胞のT管のL型Ca^<2+>チャネル電流密度の減少に百日咳毒素感受性G蛋白質(G_<i/o>)が果たす役割 (2010)
  • Author(s): 柏原俊英, 他
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪
  • Year and Date: 2010-03-17
• [Presentation] Involvement of protein phosphatases 1 and/or 2A in a decrease in the t-tubular L-type Ca^<2+> channel current density in failing myocytes. (2010)
  • Author(s): Kashihara, T., et al.
  • Organizer: The XX^<th> World Congress of the ISHR
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-03-13
• [Presentation] I_<Kr>and I_<Kr>channel suppressn cses early after depolarizations by preventing deactivation L-type Ca^<2+> channs in ventricular myocytes (2009)
  • Author(s): Yamada, M., Ohta, K., Niwa, A., Tsujino, N., akada, T. and Hirose, M
  • Organizer: The 36th International Congress of Physiological Sciences
  • Place of Presentation: Kyoto, Japan
• [Book] 心筋細胞とメカニカルストレス応答 (2009)
  • Author(s): 山田充彦、南山堂横山光宏、井上信孝
  • Publisher: 循環器ストレス学
• [Book] 循環器ストレス学 (2009)
  • Author(s): 山田充彦
  • Total Pages: 9
  • Publisher: 南山堂
• [Remarks] 大学公式ホームページ
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